I. Field of the Invention
The present invention is related generally to transdermal delivery of therapeutic agents by the use of an applied electro motive force (emf), commonly known as iontophoresis. More specifically, this invention relates to the transdermal delivery of agents such as the anti-emesis agent granisetron.
II. Related Art
The process of iontophoresis was described by LeDuc in 1908 and has since found commercial use in the delivery of ionically charged therapeutic agent molecules such as pilocarpine, lidocaine and dexamethasone. In this delivery method, ions bearing a positive charge are driven across the skin at the site of an electrolytic electrical system anode while ions bearing a negative charge are driven across the skin at the site of an electrolytic system cathode.
Earlier, and some present, iontophoretic devices have been typically constructed of two electrodes attached by adhesive materials to a patient, each connected by a wire to a remote power supply, generally a microprocessor-controlled electrical instrument. More recently, self-contained wearable iontophoretic systems have been developed. These systems are advantageous in that they do not have external wires and are much smaller in size. Examples of such systems can be found in a variety of U.S. patents, examples of which include U.S. Pat. Nos. 4,927,408; 5,358,483; 5,458,569; 5,466,217; 5,533,971; 5,605,536; 5,651,768; 5,685,837; 6,421,561; WO 00/12172; 6,653,014. These systems also include two electrodes fixed to the skin of patients by means of adhesive materials.
Unlike passive delivery patches, iontophoretic devices can incorporate an ability to modify delivery rates with simple adjustments to the magnitude of current flow. This ability can be used to create a wearable system, wherein patients can self-adjust medication delivery in accordance to individual needs. Pat. Nos. 6,171,294; 6,216,033; 6,425,892; and 6,745,071 describe iontophoretic devices where patients can self-adjust pain management dosing of fentanyl or sufentanyl using either on-demand bolus dosing or changes in continuous delivery rate.
Two-stage iontophoretic devices have also been described, where an initially high level of current can be used to induce a rapid onset of action, followed by a automated decrease in current to a lower continuous level in order to provide a “maintenance” dosage over an extended time-period. Pat. Nos. 5,207,752 and 6,421,561 are examples that serve to describe devices having such staged delivery profiles.
The present invention relates to an improved application of iontophoresis useful for the treatment of emesis. Emesis, in the form of nausea and vomiting, commonly occurs following chemotherapy, post-operatively following treatment with anesthetic agents, or after exposure to biologic agents and/or radiation, possibly in a military setting. It will be appreciated that oral dosage forms are convenient, but are unreliable because in the case of emesis, patients may be unable to keep the medication ingested.
Granisetron is a selective antagonist of 5-hydroxytryptamine (5-HT3) receptors, and commercially available in oral or injectable dosage forms. It is known to be an effective agent for the management of emesis, as both a primary dose and as a “rescue dose” medication. The term “rescue dose” is defined as an additional dose necessary to treat breakthrough or recurring symptoms. For additional information see, for example, “Dose finding study of granisetron in patients receiving high-dose cisplatin chemotherapy”, by A. Riviere in Br. J. Cancer, 69, 967-971 (1994), which provides an informative summary of clinical effectiveness of granisetron administered both as primary and rescue dosing medication.
As to the mode of administration, the disadvantage of oral administration is evident as noted above. A disadvantage of injectable administration forms lies in the invasive nature of injections, which can be painful, require clinical skill, can lead to infection, and are therefore are not suitable to self administration in a field or home setting.
Recognizing the shortcomings of oral and injectable dosage forms for granisetron, several companies have described methodologies for a transdermal administration process. Included are delivery systems for transdermal administration by passive patches, heated passive patches, passive patches applied onto RF treated skin, and spray-on-skin systems where the total amount applied is fixed and delivery is improved by co-formulated permeation enhancers.
One advantage of transdermal systems is an ability to provide a sustained release of medication over time, which may serve to provide a longer duration of action. However, a significant limitation and disadvantage of passive transdermal administration is a slow onset of sufficient action to provide relief. It is not uncommon for a passive transdermal patch to take several hours (3 or more) before a therapeutic dosage is achieved. With passive transdermal delivery, the skin can act as a depot, and release to the bloodstream will not occur until that skin depot area is saturated. This slow onset of action acts as a clinical limitation in two respects: 1) it cannot replace an existing oral or injectable form because it is a necessity to apply a patch several hours prior to a chemotherapy or operative procedure, and 2) a slow acting transdermal patch cannot reasonably serve as a rescue medication form, where a patient will prefer, for obvious reasons, a faster acting treatment. This second limitation is significant, in that it has been shown that, in many cases of highly emetogenic therapies, such as high dose chemotherapy, a significant percentage of patients will not be adequately served by a first, primary dosage form alone.
A more rapid onset of action can be achieved transdermally by using a system that includes iontophoresis. Granisetron in its hydrochloride salt form, is positively charged and can be delivered rapidly from a positively charged anode pad. Recent reports, for example, Scientific Abstract 1: Evaluation of iontophoretic permeation kinetics of granisetron through skin by subcutaneous microdialysis, presented at the 2003 AAPS meeting October, 2003; Scientific Abstract 2: IVIVC of Iontophoretic Delivery of granisetron by subcutaneous microdialysis, presented at the 2004 AAPS meeting October, 2004, have demonstrated that with iontophoresis, a therapeutic dosage can be achieved (in a hairless rat animal model) within approximately two-hours.
The two-hour system described in the reports, however, is not likely to provide additional benefit for emesis which may occur for up to several days after an exposure to an emetogenic procedure. Additionally, even the two-hour timeframe for achievement of a therapeutic dosage level is also an unacceptably long period of time necessary for clinician and patient to be waiting prior to an emetogenic treatment such as chemotherapy. Finally, the known iontophoresis patches do not provide a means to administer a second or rescue dosage for emesis management in the event the primary dosing from the patch is inadequate.
Therefore, a need exists for a simple-to-operate, inexpensive transdermal dosage form which can not only provide benefit afforded by a transdermal release of agents such as granisetron, but can also provide an initial or primary dose and one or more follow-on self-administered rescue doses treatment very rapidly.